Culprit found in antifungal drug resistance

The MSH2 gene might be responsible for the multi-drug resistance trait of the Candida glabrata pathogen, according to a new study.

Candida glabrata, accounting for about 20–25% of Candida fungal infections, is known for developing rapid resistance to antifungal drugs. However, the mechanism behind this characteristic behaviour had been unclear, until this study1.

An international team of scientists, including researchers from Hamad Medical Corporation in Qatar, suggests that a loss-of-function mutation in the MSH2 gene, implicated in repairing defects affecting the DNA, is very possibly the reason behind the drug resistance of Candida glabarata.

Disrupting the MSH2 gene increased the resistance to antifungal drugs, such as fluconazole and echinocandins, by 9- to 82-fold when compared to the wild-type strain.

The team also analysed isolated strains from 357 patients. Remarkably, MSH2 mutations were detected in 65% of the fluconazole-resistant strains and 62% of the strains showing resistance to both fluconazole and echinocandin.

Those results were also confirmed in mice, where the group colonized with the MSH2-disrupted strain showed increased resistance to treatment, in contrast to the mice colonized with the wild-type strain.

“Our findings provide a molecular basis to explain how distinct resistance mechanisms can emerge rapidly during therapy. It furthers raises the suggestion that aspects of clinical practice may be selecting for these mutator genotypes, which is of concern for downstream therapy,” says David Perlin from the Public Health Research Institute at New Jersey Medical School, USA.